Cardiovascular disease remains the single most common cause of natural death in developed countries. Sudden cardiac death (also commonly referred to as “death outside hospital”, “dead on arrival” or “dead in emergency”) from cardiac causes has been estimated to account for approximately 50 percent of all deaths from cardiovascular causes. A common cause of sudden cardiac death is ventricular arrhythmia, including, for example, ventricular tachycardia, in which the resting heart rate is faster than normal; ventricular fibrillation, in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making the muscles quiver rather than contract properly; or an arrhythmic condition in which both ventricular tachycardia and ventricular fibrillation are present. Ventricular arrhythmia is often triggered by acute coronary events, occurring in persons with or without known cardiac disease or in association with structural heart abnormalities.
Several molecular mechanisms underlying heart diseases have been elucidated by studying the role of gap junctions. Gap junctions are channels that permit intercellular communication. In mammalian tissues, these channels are ubiquitously expressed and serve diverse biological functions (Saez 2003). Within the heart, gap junctions are essential for propagation of electrical activity that is required for cardiac function. In addition, gap junction remodelling occurs in heart disease and may contribute to the pathophysiology of cardiac arrhythmias.
Functional gap junctions are composed of two hemichannels each contributed by two adjacent cells (Saez 2003). Each hemichannel is made up of six connexin (Cx) proteins. Protein assembly can result in homo- or hetero-meric channels. Of the 20 connexins in vertebrates, the most abundant connexins in the heart are Cx37, Cx40, Cx43, and Cx45. Cx37, Cx40 and Cx43 are involved in cardiac electrical impulse propagation and cardiogenesis. Cx45 is essential for embryonic heart development and may not be at all necessary for normal cardiac function post-natally. In this respect, Bao et al. (2011) recently reported that activation and conduction are not altered in Cx45-overexpressing hearts and that no difference in conduction velocity or patterns were identified in Cx45-deficient hearts.
Contemporary clinical management of ventricular arrhythmia consists of pharmacological agents and device-based electrical therapy. Drugs are of moderate efficacy and do not, in most patients, obviate the need for a prophylactic implantable cardio-defibrillator. In addition, many drugs used to prevent ventricular tachycardia and/or ventricular fibrillation have serious side-effects including pro-arrhythmia. Implantable cardio-defibrillators are effective in detecting ventricular tachycardia and/or ventricular fibrillation by either anti-tachycardia pacing or defibrillation however there are numerous disadvantages to using implantable cardio-defibrillators such as the morbidity associated with implantation and maintenance of the hardware, in addition to the pain of receiving direct current shocks while conscious, anticipatory anxiety of future shocks and cost.
Accordingly, there remains an unmet need for methods and compositions for the treatment of myocardial infarction-related complication, cardiac disorders characterised by abnormal conduction, arrhythmias and other cardiac conditions.